EP1740567A1 - Process for the manufacture of tocopheryl acylates - Google Patents
Process for the manufacture of tocopheryl acylatesInfo
- Publication number
- EP1740567A1 EP1740567A1 EP05736077A EP05736077A EP1740567A1 EP 1740567 A1 EP1740567 A1 EP 1740567A1 EP 05736077 A EP05736077 A EP 05736077A EP 05736077 A EP05736077 A EP 05736077A EP 1740567 A1 EP1740567 A1 EP 1740567A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tocopherol
- process according
- acylating agent
- acid
- alkaline earth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 title description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 43
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims abstract description 32
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000007787 solid Substances 0.000 claims abstract description 23
- 239000011732 tocopherol Substances 0.000 claims abstract description 23
- 229930003799 tocopherol Natural products 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 14
- 229960001295 tocopherol Drugs 0.000 claims abstract description 14
- 235000010384 tocopherol Nutrition 0.000 claims abstract description 13
- -1 tocopheryl acylate Chemical compound 0.000 claims abstract description 12
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 9
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 44
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 27
- 229910052593 corundum Inorganic materials 0.000 claims description 27
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 27
- 229940087168 alpha tocopherol Drugs 0.000 claims description 18
- 229960000984 tocofersolan Drugs 0.000 claims description 18
- 239000002076 α-tocopherol Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052681 coesite Inorganic materials 0.000 claims description 12
- 229910052906 cristobalite Inorganic materials 0.000 claims description 12
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 229910052682 stishovite Inorganic materials 0.000 claims description 12
- 229910052905 tridymite Inorganic materials 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000002478 γ-tocopherol Substances 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 150000008065 acid anhydrides Chemical group 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 abstract description 13
- 238000005917 acylation reaction Methods 0.000 abstract description 13
- 235000019149 tocopherols Nutrition 0.000 abstract description 9
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 abstract description 9
- 239000011575 calcium Substances 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 229910052791 calcium Inorganic materials 0.000 description 13
- 238000004821 distillation Methods 0.000 description 13
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 235000004835 α-tocopherol Nutrition 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- DFUSDJMZWQVQSF-XLGIIRLISA-N (2r)-2-methyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 DFUSDJMZWQVQSF-XLGIIRLISA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229930003427 Vitamin E Natural products 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 4
- 229940042585 tocopherol acetate Drugs 0.000 description 4
- 229940046009 vitamin E Drugs 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- BYFGZMCJNACEKR-UHFFFAOYSA-N aluminium(i) oxide Chemical compound [Al]O[Al] BYFGZMCJNACEKR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001181 organosilyl group Chemical class [SiH3]* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- PZZKGQBMBVYPGR-UHFFFAOYSA-N η-tocopherol Chemical compound OC1=C(C)C=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 PZZKGQBMBVYPGR-UHFFFAOYSA-N 0.000 description 2
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000006842 Henry reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000006668 aldol addition reaction Methods 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Inorganic materials [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002734 clay mineral Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000007278 cyanoethylation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Inorganic materials [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000019355 sepiolite Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229930003802 tocotrienol Natural products 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07G—COMPOUNDS OF UNKNOWN CONSTITUTION
- C07G13/00—Vitamins
Definitions
- the present invention is concerned with a novel process for the acylation of tocopherols and the use of specific catalysts therein.
- tocopherol as used herein is to be understood to refer to any compound derived from the basic structure of tocol [2-methyl-2-(4',8',12'-trimethyltridecyl)-6- chromanol], having a free 6-hydroxy group and exhibiting vitamin E activity, viz.
- any tocopherol having the saturated side chain 4',8',12'-trimethyltridecyl such as ⁇ -, ⁇ -, ⁇ -, ⁇ 2 — or ⁇ -tocopherol
- any tocotrienol having three double bonds in the side chain [4',8',12'-trimethyltridec-3',7',ll'-trienyl] such as ⁇ - or ⁇ i- tocopherol.
- various tocopherols (all-r ⁇ c)- ⁇ -tocopherol generally referred to as vitamin E, is of primary interest, being the most active and industrially most important member of the vitamin E group.
- the present invention is preferably concerned with a novel process for the manufacture of acylates of tocopherols (tocopheryl acylates), more particularly of tocopheryl acetates.
- the present invention is concerned with a process for the manufacture of (all-r ⁇ c)- ⁇ -tocopheryl acetate, since this is the main commercial form of vitamin E.
- ⁇ -Tocopherol itself and the other tocopherols such as those mentioned above can be readily acylated by the process of the present invention.
- each of the tocopherols can be acylated in the form of its racemate or of any individual stereoisomer.
- the novel process according to the present invention provides excellent yields, avoids corrosion problems, can be carried out in the absence of an additional solvent, thus avoiding the need to recycle solvents, and can be carried out in a continuous or batchwise mode.
- a process for the manufacture of an acylate of a tocol e.g., tocotrienyl acylate or a tocopheryl acylate
- a solid basic catalyst comprising an alkali metal and/or alkaline earth metal, preferably on a solid carrier.
- the acylation can be carried out in principle using any acylating agent conventionally used for the acylation of a phenolic hydroxyl group as is present in tocopherols.
- acylating agents are acid anhydrides and acyl halides.
- the acyl groups in such acylating agent may be derived from aliphatic carboxylic acids, e.g.
- alkanoic acids from linear or branched chain alkanoic acids, in particular C ⁇ - -alkanoic acids such as acetic acid, propionic acid, butyric acid and pivalic acid, or from higher alkanoic acids (fatty acids) with up to 20 carbon atoms such as palmitic acid; or from aromatic carboxylic acids, particularly benzoic acid, so that in each case the appropriate acylate, being an alkanoate, or e.g. the benzoate, respectively, of tocol or the tocopherol is produced in the acylation process.
- C ⁇ - -alkanoic acids such as acetic acid, propionic acid, butyric acid and pivalic acid
- higher alkanoic acids fatty acids
- palmitic acid fatty acids
- aromatic carboxylic acids particularly benzoic acid
- aliphatic acyl halides are linear or branched chain alkanoyl chlorides such as acetyl, propionyl and butyryl chloride, and, of aromatic acyl halides, benzoyl chloride.
- the preferred acylating agent is acetic anhydride or acetyl chloride, most preferably acetic anhydride.
- the acylation in accordance with the process of the present invention may by carried out in the presence or in the absence of an added solvent, but preferably one of the reactants, i.e. the tocol or tocopherol or the acylating agent, is used in excess and no added solvent used.
- the acylating agent is used in excess, preferably in a one- to about a threefold molar amount, more preferably in a 1.5- to 2.5-fold molar amount, and most preferably in a 1.75- to 2.25-fold molar amount, relative to the molar amount of tocol or tocopherol present in the initial reaction mixture.
- an additional solvent is used, however, this is suitably a polar or non-polar aprotic organic solvent, particularly an aliphatic, preferably C to do aliphatic, hydrocarbon, e.g. pentane, hexane, heptane or decane; an alicyclic, preferably C 4 to C alicyclic, hydrocarbon, e.g. cyclohexane; or an aromatic, particularly C 6 to o aromatic, hydrocarbon, e.g. benzene, toluene, an xylene or naphthalene.
- a polar or non-polar aprotic organic solvent particularly an aliphatic, preferably C to do aliphatic, hydrocarbon, e.g. pentane, hexane, heptane or decane; an alicyclic, preferably C 4 to C alicyclic, hydrocarbon, e.g. cyclohexane; or an aromatic, particularly C 6 to
- the following types of basic catalysts can be used in the reaction of the present invention: alkali and alkaline metals; alkali metal oxides and alkaline earth metal oxides; alkali and alkaline earth metal oxides on solid supports; alkali metal amides and fluorides; zeolithes (alkali ion-exchanged and alkali ion-added zeolithes) and clay minerals (hydrotalcites, chrysotiles and sepiolites).
- zeolithes alkali ion-exchanged and alkali ion-added zeolithes
- clay minerals hydrotalcites, chrysotiles and sepiolites.
- alkali metals used in the solid catalysts of the present invention are Na, K, Rb and Cs
- examples of alkaline earth metals are Mg, Ca, Sr and Ba.
- One or several alkali and/or alkaline earth metals in combination with each other in different weight ratios (since they are not critical) can be used.
- at least one alkali metal and at least one alkaline earth metal is used, e.g., Na + Ca.
- the weight ratios of metal : carrier material are not critical either and can vary within wide ranges. They can be, e.g. in the range of 0.1 - 70% and are preferably in the range of 1 - 10% if one metal is used and 30 - 60% if more than one metal is used.
- All normally useful carriers can be used as support for the metals, such as activated carbon, silica gel, diatomite, alumina, talc, silicates and kaolin with SiO 2 , Al 2 O and TiO 2 being preferred.
- the catalysts are commercially available. Alternatively, they can be prepared as described in the literature or in analogy to methods well-known in the art, e.g., as described by Ono, Y. and Baba, T. in Catalysis Today 38, 321 - 337 (1997) and in references cited therein, which article is incorporated herein by reference. Catalysts 1 - 19 and 20 - 25 (Tables 1 and 2, below) have been prepared and provided by Degussa AG, Hanau, Germany.
- the catalyst is prepared from an aqueous solution of an alkali or alkaline earth metal salt, such as a hydroxide, carbonate, nitrate, chloride, acetate or silicate.
- the solid carrier is doped with the metal salt in a manner known per se, e.g., by impregnation, soaking or ion-exchange.
- the wet material is then dried and calcined at a temperature in the range of 150°C and 800°C, preferably 200°C - 700°C and most preferably 300°C - 650°C.
- the desired final concentration of the metal ions in the catalyst is achieved empirically by using correspondingly concentrated aqueous solutions.
- Catalysts can also be prepared by mixing or moulding the solid components with each other with or without addition of solvents. h a preferred embodiment of the invention the solid base catalyst is added to the reaction mixture in pure solid form without further activation or modification.
- the amount of catalyst used is based on the amount of the reactant, i.e. the tocopherol or the acylating agent, usually the former, which is used in the lesser molar amount and is suitably in the range from about 0.005 to about 15 mmol, preferably from about 0.0 lto about 1.0 mmol, based on said lesser molar amount, when the process is effected in a batchwise operational mode per 38.4 mmol tocol.
- the relative amount of catalyst will have to be adjusted to the size of the reactor and the flow of the reactants.
- the determination of the appropriate relative amount based on the figures for the batchwise operational mode is within the normal skill of the production chemist.
- the acylation process in accordance with the present invention is conveniently carried out at temperatures from about 80°C to about 120°C, preferably from about 90°C to about 110°C. Moreover, the process is conveniently carried out under an inert gas atmosphere, preferably under gaseous nitrogen or argon, especially the former.
- the progress of the reaction is suitably monitored by analytical means, such as gas chromatography of samples taken from the reaction mixture at various time intervals during the reaction.
- analytical means such as gas chromatography of samples taken from the reaction mixture at various time intervals during the reaction.
- the produced tocopheryl acylate can be isolated by distilling off, preferably under reduced pressure, acylating agent, and the secondary product formed in the acylation, e.g., acetic acid when acetic anhydride is used as the acylating agent, followed by further distillation, also preferably under reduced pressure, to collect as pure a fraction of the desired acylation product as required.
- the main advantage of the use of the catalysts of the present invention in the acylation of tocopherols is that no epimerization of the chromane center occurs when starting from optically pure tocopherol and that with specific catalysts, e.g., those comprising Na + Ca, reaction time can be reduced considerably.
- Example 1 illustrates the present invention in more detail.
- a 10% Ca on Al 2 O 3 catalyst (obtained in an analogous way as described under (a)) was soaked with an appropriate sodium silicate solution in an analogous way, dried and calcined for 2 hours at 500°C to yield the catalyst with the desired concentration of sodium and calcium.
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Abstract
Description
Claims
Priority Applications (1)
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EP05736077A EP1740567B1 (en) | 2004-04-26 | 2005-04-18 | Process for the manufacture of tocopheryl acylates |
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EP04009816 | 2004-04-26 | ||
EP05736077A EP1740567B1 (en) | 2004-04-26 | 2005-04-18 | Process for the manufacture of tocopheryl acylates |
PCT/EP2005/004068 WO2005103026A1 (en) | 2004-04-26 | 2005-04-18 | Process for the manufacture of tocopheryl acylates |
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EP1740567B1 EP1740567B1 (en) | 2007-08-22 |
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US (1) | US7435836B2 (en) |
EP (1) | EP1740567B1 (en) |
JP (1) | JP4874236B2 (en) |
KR (1) | KR101174174B1 (en) |
CN (1) | CN1946706B (en) |
AT (1) | ATE370939T1 (en) |
DE (1) | DE602005002136T2 (en) |
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DE112007003075T5 (en) | 2006-12-27 | 2009-12-17 | Dsm Ip Assets B.V. | Process for the acylation of organic hydroxy compounds |
US8796809B2 (en) | 2008-09-08 | 2014-08-05 | Cree, Inc. | Varactor diode with doped voltage blocking layer |
BR112020024695A2 (en) | 2018-06-05 | 2021-03-02 | Flagship Pioneering Innovations V, Inc | active agents and methods of using these for the treatment of metabolic disorders and non-alcoholic fatty liver disease |
WO2020007856A1 (en) * | 2018-07-02 | 2020-01-09 | Dsm Ip Assets B.V. | Process for the selective acylation of primary hydroxy groups in the presence of secondary hydroxy groups and catalyst therefor |
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JPS4955633A (en) * | 1972-07-30 | 1974-05-30 | ||
DE4243464A1 (en) * | 1992-12-22 | 1994-06-23 | Basf Ag | Process for the preparation of alpha-tocopherol and alpha-tocopheryl acetate in liquid or supercritical carbon dioxide |
DE19603142A1 (en) * | 1996-01-29 | 1997-07-31 | Basf Ag | Tocopherol and tocopheryl acetate production |
JP2002502360A (en) * | 1996-01-29 | 2002-01-22 | ビーエーエスエフ アクチェンゲゼルシャフト | Method for producing dlα-tocopherol or dl-α-tocopheryl acetate |
DE10011402A1 (en) * | 2000-03-09 | 2001-09-13 | Degussa | Process for the preparation of alpha-tocopherol esters |
WO2002042286A1 (en) * | 2000-11-22 | 2002-05-30 | Basf Aktiengesellschaft | Method for continuously acylating chromanol ester derivatives |
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KR20070015550A (en) | 2007-02-05 |
TW200538448A (en) | 2005-12-01 |
CN1946706A (en) | 2007-04-11 |
KR101174174B1 (en) | 2012-08-14 |
CN1946706B (en) | 2012-03-21 |
JP2007534713A (en) | 2007-11-29 |
US7435836B2 (en) | 2008-10-14 |
US20070225509A1 (en) | 2007-09-27 |
ATE370939T1 (en) | 2007-09-15 |
TWI347319B (en) | 2011-08-21 |
WO2005103026A1 (en) | 2005-11-03 |
DE602005002136T2 (en) | 2008-05-21 |
JP4874236B2 (en) | 2012-02-15 |
DE602005002136D1 (en) | 2007-10-04 |
EP1740567B1 (en) | 2007-08-22 |
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